Composition for external use

Abstract

To provide a composition for external use which is an emulsion and suppresses separation between a water phase and an oil phase.SOLUTION: There is provided a composition for external use which comprises an antihistaminic agent and a vegetable oil and is an emulsion. The antihistaminic agent preferably is diphenhydramine or a salt thereof and the essential oil preferably is lavender oil and eucalyptus oil. Furthermore, the composition may contain a topical anesthetic. The emulsion preferably is an oil-in-water type. The composition may contain 1 to 95 wt.% of water, based on the total amount of the composition.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for external use that has excellent stability. [Background technology]

[0002] As the dosage form of a composition for external use such as medicine, a solid, a powder, a liquid, a liniment, a lotion, a cream, an ointment, a gel, a spray, a patch, etc. are used. Among them, a cream is a semi-solid preparation containing an oily substance and an aqueous substance and emulsified into an oil-in-water type or a water-in-oil type. In addition, a lotion includes an emulsion lotion, a solution lotion, a suspension lotion, etc., and an emulsion lotion is a liquid or fluid preparation emulsified into an oil-in-water type or a water-in-oil type. Such an emulsion has the advantages of good usability, good spreadability, and the ability to be washed off with water, and is widely used as a dosage form of a composition for external use. However, emulsions require some ingenuity to keep the emulsion stable, since the aqueous phase and the oil phase may separate over time. For this reason, surfactants are often added, but high concentrations of surfactants have problems such as skin irritation, and from this perspective, it is desirable to limit the amount added. In addition, in oil-in-water emulsions, thickeners are added to improve the viscosity of the aqueous phase, thereby suppressing the separation of the aqueous phase and the oil phase, but the addition of high concentrations of thickeners can increase stickiness and impair the feel of use.

[0003] For this reason, many attempts have been made to improve the stability of emulsions. For example, Patent Document 1 teaches that by incorporating a disintegrant, such as crospovidone, carmellose, croscarmellose, or carboxymethyl starch, which is usually incorporated into solid preparations, into an oil-in-water emulsion composition, separation over time, particularly in a high-temperature environment, can be suppressed. However, there is a demand for emulsion stabilization techniques that are suitable for the type of active ingredient, etc.

[0004] Here, unlike animal oils and mineral oils, vegetable oils are often liquid at room temperature, have a small molecular weight so they easily penetrate the skin, do not easily form a film on the skin so they are less likely to interfere with excretion from sweat glands and sebaceous glands, and further have the advantage that they themselves contain useful ingredients such as vitamins, minerals, and antioxidants, and therefore are widely used as components of external compositions. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2010-254627 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a composition for external use that is an emulsion, in which separation of an aqueous phase and an oily phase is suppressed. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have obtained the following findings. Emulsions containing antihistamines or vegetable oils tend to be unstable. However, unexpectedly, in the case of an emulsion containing both an antihistamine and vegetable oil, the two components act synergistically to improve the stability of the emulsion.

[0008] The present invention has been completed based on the above findings, and provides the following composition for external use. Item 1. A composition for external use which is an emulsion and contains an antihistamine and a vegetable oil. Item 2. The composition for external use according to Item 1, wherein the antihistamine is at least one selected from the group consisting of ethanolamine antihistamines and propylamine antihistamines. Item 3. The composition for external use according to Item 1 or 2, wherein the content of the antihistamine is 0.01 to 5% by weight based on the total amount of the composition. Item 4. The composition for external use according to any one of Items 1 to 3, wherein the vegetable oil is an essential oil. Item 5. The composition for external use according to any one of Items 1 to 4, wherein the content of the vegetable oil is 0.0001 to 1 wt % based on the total amount of the composition. Item 6. The composition for external use according to any one of Items 1 to 5, further comprising a local anesthetic. Item 7. The composition for external use according to Item 6, wherein the content of the local anesthetic is 0.01 to 5% by weight based on the total amount of the composition. Item 8. The composition for external use according to any one of Items 1 to 7, which is an oil-in-water emulsion. Item 9. The composition for external use according to any one of Items 1 to 8, wherein the composition contains 0.1 to 95 wt % of water based on the total amount of the composition. Item 10. The composition for external use according to any one of Items 1 to 9, which is a cream or a lotion. Item 11. The composition for external use according to any one of Items 1 to 10, which is a composition for external use on the skin. Effect of the Invention

[0009] The topical composition of the present invention contains a vegetable oil and an antihistamine, which improves the stability of the emulsion state. The topical composition of the present invention has improved stability of the emulsion state against not only heat but also light. The composition of the present invention can improve the stability of an emulsion without relying solely on the incorporation of additives such as surfactants and thickeners that are not necessary for the medicinal effect, or without relying on these additives, thereby allowing for greater freedom in formulation.

[0010] In addition, since the topical composition of the present invention contains an antihistamine, it is suitable for treating, preventing, or improving diseases exhibiting symptoms caused by itching or dry skin. In addition, by containing vegetable oil (particularly, essential oil), it is expected that the preparation will have a fragrance to enhance the relaxing effect and relieve stress caused by itching, etc. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention will be described in detail below. The topical composition of the present invention is an emulsion that contains an antihistamine and a vegetable oil.

[0012] Antihistamines Examples of antihistamines include ethanolamine antihistamines such as diphenhydramine, bromodiphenhydramine, clemastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, and phenyltoloxamine; propylamine antihistamines such as chlorpheniramine, dimethindene, and talastine; ethylenediamine antihistamines such as mepyramine, methapyrilene, and tripelennamine; phenothiazine antihistamines such as alimemazine, hydroxyethylpromethazine, isothipendyl, mequitazine, oxomemazine, and promethazine; piperazine antihistamines such as aztreonine, cetirizine, homochlorcyclizine, cyclizine, hydroxyzine, levocetirizine, meclizine, and oxatomide, ketotifen, olopatadine, fexofenadine, loratadine, terfenadine, antazoline, azatadine, bamipine, cyproheptadine, deptropine, ebastine, emedastine, epinastine, mebhydroline, mizolastine, pimethixene, pyrobutamine, quifenadine, rupatadine, triprolidine, acrivastine, astemizole, azelastine, bilastine, desloratadine, and salts thereof.

[0013] The salt may be any pharma- ceutically or physiologically acceptable salt, and examples of the salt include inorganic acid salts and organic acid salts. Examples of inorganic acid salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc. Examples of organic acid salts include monocarboxylates such as acetate, trifluoroacetate, butyrate, palmitate, and stearate, polycarboxylates such as fumarate, maleate, succinate, and malonate, oxycarboxylates such as lactate, tartrate, and citrate, and organic sulfonates such as methanesulfonate, toluenesulfonate, tosylate, and napadisilate. Specifically, diphenhydramine hydrochloride, bromodiphenhydramine hydrochloride, clemastine maleate, chlorphenoxamine hydrochloride, diphenylpyraline hydrochloride, doxylamine succinate, orphenadrine hydrochloride, chlorpheniramine maleate, dimethindene maleate, methapyrilene hydrochloride, tripelennamine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, cetirizine hydrochloride, homochlorcyclizine hydrochloride, cyclizine hydrochloride, and hydroxyzine hydrochloride. , levocetirizine hydrochloride, meclizine hydrochloride, ketotifen fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, antazoline hydrochloride, azatadine maleate, cyproheptadine hydrochloride, deptropinc citrate, emedastine fumarate, epinastine hydrochloride, mebhydroline napadisilate, pimethixene maleate, pyrobutamine phosphate, quifenadine hydrochloride, rupatadine fumarate, triprolidine hydrochloride, and azelastine hydrochloride. Antihistamines that are salts can be hydrated, hemihydrate, or anhydrous.

[0014] Among these, amine antihistamines such as ethanolamine, propylamine, and ethylenediamine are preferred, ethanolamine and propylamine antihistamines are more preferred, ethanolamine antihistamines are even more preferred, diphenhydramine or a salt thereof (particularly an inorganic acid salt such as hydrochloride) is even more preferred, and diphenhydramine and diphenhydramine hydrochloride are particularly preferred. The antihistamines can be used alone or in combination of two or more.

[0015] The content of the antihistamine is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, even more preferably 0.1% by weight or more, even more preferably 0.5% by weight or more, and particularly preferably 0.8% by weight or more, based on the total amount of the composition. Also, it is preferably 5% by weight or less, more preferably 3% by weight or less, even more preferably 2% by weight or less, even more preferably 1.5% by weight or less, and particularly preferably 1.1% by weight or less. 1% by weight is the most preferable. Within this range, an appropriate antihistamine effect can be exhibited and the stability of the emulsified state of the composition can be sufficiently improved.

[0016] vegetable oil Vegetable oils include lavender oil, eucalyptus oil, rosemary oil, rosehip oil, Roman chamomile oil, chamomile oil (chamomile oil), mint oil, mentha piperita oil, peppermint oil, spearmint oil, vetiver oil, lithodia cubica oil, lemon oil, sandalwood oil, nutmeg oil, cinnamon oil, hyssop oil, caraway oil, orange oil, cade oil, bergamot oil, grapefruit oil, lime oil, salvia oil, thyme oil, clove oil, aloe oil, jasmine oil, neroli oil, rose oil, camphor oil, geranium oil, sandalwood oil, and isopropyl alcohol. Essential oils include: nigrum oil, melissa oil, basil oil, patchouli oil, juniper oil, juniper berry oil, sage oil, black pepper oil, marjoram oil, amyris oil, mugwort oil, wormwood oil, angelica oil, ginger oil, allspice oil, cascarilla oil, calamus oil, clary sage oil, celery oil, tea tree oil, carrot oil, patchouli oil, vetiver oil, hops oil, mastic oil, myrrh oil, labdanum oil, turmeric oil, origanum oil, galangal oil, citronella oil, bay oil, yarrow oil, pimento berry oil, and lovage oil.

[0017] Also usable are vegetable oils that are non-volatile at room temperature, such as sunflower oil, evening primrose oil, almond oil, olive oil, avocado oil, jojoba oil, corn oil, soybean oil, mallow oil, grapeseed oil, sesame oil, hazelnut oil, purselin oil, palm oil, castor oil, walnut oil, cashew nut oil, sweet almond oil, kukui nut oil, safflower oil, camellia oil, macadamia nut oil, sasanqua oil, peanut oil, medfoam oil, rice cup sprout oil, and squalane.

[0018] Among these, essential oils are preferred for the present invention, since they have a particularly high effect of stabilizing the emulsified state in the composition of the present invention, and can be expected to enhance the relaxing effect by imparting a scent to the preparation and to relieve stress caused by itching, etc. In particular, lavender oil, eucalyptus oil, bergamot oil, and chamomile oil are preferred, with lavender oil and eucalyptus oil being more preferred. The vegetable oils may be used alone or in combination of two or more.

[0019] The content of the vegetable oil is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, even more preferably 0.005% by weight or more, and even more preferably 0.01% by weight or more, based on the total amount of the composition. It can also be 0.03% by weight or more, and especially 0.05% by weight or more. It can also be 1% by weight or less, more preferably 0.5% by weight or less, and even more preferably 0.2% by weight or less. It can also be 0.1% by weight or less. Within this range, the stability of the emulsion state of the composition can be sufficiently improved, and an appropriate fragrance can be imparted.

[0020] When the vegetable oil is lavender oil, since lavender oil contains a large amount of linalool acetate, the content of lavender oil can be specified by the content of linalool acetate. It is preferable that lavender oil is contained so that the concentration of linalool acetate relative to the total amount of the composition is 0.0001% by weight or more, particularly 0.0005% by weight or more, particularly 0.001% by weight or more, particularly 0.0025% by weight or more. It can also be contained so that the concentration of linalool acetate relative to the total amount of the composition is 0.01% by weight or more. It is also preferable that lavender oil is contained so that the concentration of linalool acetate relative to the total amount of the composition is 1% by weight or less, particularly 0.5% by weight or less, particularly 0.1% by weight or less, particularly 0.05% by weight or less.

[0021] When the vegetable oil is eucalyptus oil, since eucalyptus oil contains a large amount of cineole, the content of eucalyptus oil can be specified by the content of cineole. Eucalyptus oil is preferably contained so that the concentration of cineole relative to the total amount of the composition is 0.0001% by weight or more, particularly 0.0005% by weight or more, particularly 0.001% by weight or more, particularly 0.005% by weight or more. Also, an embodiment in which cineole is contained so that the concentration of cineole relative to the total amount of the composition is 0.01% by weight or more, particularly 0.05% by weight or more can be exemplified. Also, eucalyptus oil is preferably contained so that the concentration of cineole relative to the total amount of the composition is 1% by weight or less, particularly 0.5% by weight or less, particularly 0.1% by weight or less.

[0022] The content ratio of the vegetable oil to the antihistamine in the topical composition of the present invention is not particularly limited, and can be appropriately set depending on the types of the antihistamine and the vegetable oil, the types and contents of other blended ingredients, the application of the topical composition, the formulation form, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the vegetable oil to the antihistamine is, for example, preferably 0.0001 to 5 parts by weight, more preferably 0.001 to 1 part by weight, even more preferably 0.005 to 0.5 parts by weight, and particularly preferably 0.01 to 0.2 parts by weight, of the total content of the vegetable oil relative to 1 part by weight of the total content of the antihistamine.

[0023] Local anesthetics The compositions of the present invention may include a local anesthetic. Examples of local anesthetics include local anesthetics having an amine structure or an amide structure such as lidocaine, dibucaine, mepivacaine, bupivacaine, ropivacaine, levobupivacaine, oxethazaine, and salts thereof; local anesthetics having an amine structure or an ester structure such as cocaine, procaine, chloroprocaine, tetracaine, and salts thereof; and local anesthetics having an ester structure such as ethyl aminobenzoate and oxypolyethoxydodecane.

[0024] The salt may be any pharma- ceutically or physiologically acceptable salt, and examples of the salt include inorganic acid salts and organic acid salts. Examples of inorganic acid salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc. Examples of organic acid salts include monocarboxylates such as acetate, trifluoroacetate, butyrate, palmitate, and stearate, polycarboxylates such as fumarate, maleate, succinate, and malonate, oxycarboxylates such as lactate, tartrate, and citrate, and organic sulfonates such as methanesulfonate, toluenesulfonate, tosylate, and napadisilate. Specific examples include lidocaine hydrochloride, dibucaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, ropivacaine hydrochloride, levobupivacaine hydrochloride, oxethazaine hydrochloride, cocaine hydrochloride, procaine hydrochloride, chloroprocaine hydrochloride, and tetracaine hydrochloride. Local anesthetics that are salts can be hydrated, hemihydrate, or anhydrous.

[0025] Among these, lidocaine, dibucaine, ethyl aminobenzoate, oxypolyethoxydodecane, or a salt thereof (such as hydrochloride) is preferred, lidocaine or a salt thereof is more preferred, lidocaine or lidocaine hydrochloride is even more preferred, and lidocaine is even more preferred. The local anesthetics can be used alone or in combination of two or more.

[0026] The content of the local anesthetic is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, even more preferably 0.1% by weight or more, and even more preferably 0.5% by weight or more, based on the total amount of the composition. It can also be 1% by weight or more. It is preferably 5% by weight or less, more preferably 3% by weight or less, and even more preferably 2% by weight or less. Within this range, the local anesthetic effect is effectively exerted and the stability of the emulsion of the present invention is sufficiently improved.

[0027] The content ratio of the local anesthetic to the antihistamine in the topical composition of the present invention is not particularly limited, and can be appropriately set depending on the types of antihistamine and local anesthetic, the types and contents of other blended ingredients, the application of the topical composition, the formulation form, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the local anesthetic to the antihistamine is, for example, preferably 0.01 to 20 parts by weight, more preferably 0.05 to 10 parts by weight, even more preferably 0.1 to 5 parts by weight, and particularly preferably 0.2 to 2.5 parts by weight, of the total content of the local anesthetic relative to 1 part by weight of the total content of the antihistamine.

[0028] Antipruritic The compositions of the present invention may further comprise an antipruritic agent other than an antihistamine. Antipruritic agents other than antihistamines include crotamiton, ichthammol, mocthal, thymol, and salts thereof. The salt may be any pharma- ceutically or physiologically acceptable salt, and examples of the salt include inorganic acid salts and organic acid salts. Examples of inorganic acid salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc. Examples of organic acid salts include monocarboxylates such as acetate, trifluoroacetate, butyrate, palmitate, and stearate, polycarboxylates such as fumarate, maleate, succinate, and malonate, oxycarboxylates such as lactate, tartrate, and citrate, and organic sulfonates such as methanesulfonate, toluenesulfonate, tosylate, and napadisilate. Antipruritic agents that are salts can be hydrated, hemihydrate, or anhydrous. Of these, crotamiton is preferred. Antipruritic agents other than antihistamines can be used alone or in combination of two or more.

[0029] The content of the antipruritic agent other than the antihistamine is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, even more preferably 1% by weight or more, and even more preferably 3% by weight or more, based on the total amount of the composition. Also, it is preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less. Within this range, the antipruritic effect is effectively exerted and the effect of the present invention is fully exhibited.

[0030] Other Ingredients The composition of the present invention can be prepared as a topical composition for a drug, quasi-drug, or cosmetic by mixing the components including the antihistamine and the vegetable oil with a base or carrier used in a drug, quasi-drug, or cosmetic, and, if necessary, with an additive or other physiologically or pharmacologically active ingredient. In particular, the composition can be a pharmaceutical composition (topical composition).

[0031] Examples of additives include surfactants, thickeners, preservatives, pH adjusters, stabilizers or chelating agents, ultraviolet absorbing agents or ultraviolet scattering agents, irritation reducing agents, and colorants. The additives may be used alone or in combination of two or more. Moreover, additives can be used within a range that does not impair the effects of the present invention.

[0032] Examples of surfactants include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexyl acid, and diglycerol sorbitan tetra-2-ethylhexyl acid, glycerin fatty acids such as glycerin monostearate and glycerin monostearate malic acid, polyglycerin fatty acids such as polyglyceryl monoisostearate and polyglyceryl diisostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil), and the like. hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 80, etc.; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), etc.; polyoxyethylene monococoate glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether (cetomacrogol), stearylamine, oleylamine, etc. The surfactant can be blended in an amount of, for example, 0.1 to 20% by weight, and preferably 1 to 10% by weight, based on the total amount of the composition.

[0033] Examples of thickeners include thickening polysaccharides (guar gum, locust bean gum, carrageenan, xanthan gum, dextran, etc.), cellulose-based thickeners (methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), alginic acid, its salts, and its derivatives (alginic acid, sodium alginate, propylene glycol alginate, etc.), vinyl-based thickeners (polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, acrylic acid / methacrylic acid alkyl copolymer, sodium polyacrylate, etc.), bentonite, dextrin fatty acid esters, pectin, etc. The thickener can be blended in an amount of, for example, 0.01 to 10% by weight, and preferably 0.1 to 5% by weight, based on the total amount of the composition.

[0034] Preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate, phenoxyethanol, BHT and the like.

[0035] Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, sodium succinate, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), and the like.

[0036] Stabilizing or chelating agents include sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, and the like.

[0037] Examples of ultraviolet absorbing agents or ultraviolet scattering agents include 2-ethylhexyl paramethoxycinnamate, 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid hexyl ester, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, t-butylmethoxydibenzoylmethane, dibenzylidene dioxoimidazolidine propylonate ethylhexyl, ethylhexyl triazoline, paraaminobenzoic acid and its derivatives, octyl paradimethylaminobenzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, and zinc oxide.

[0038] Irritation reducers include licorice extract, sodium alginate, etc.

[0039] Examples of coloring agents include the dyes listed in the Legal Dyes Handbook (edited by the Japan Cosmetic Industry Association (2004)).

[0040] Other physiologically active or pharmacologically active ingredients (physiologically active or pharmacologically active ingredients other than antihistamines, local anesthetics, and antipruritic agents that are not antihistamines) include, for example, anti-inflammatory agents, bactericides, antifungal agents, moisturizing ingredients, vitamins, peptides or derivatives thereof, blood circulation promoting ingredients, cell activating ingredients, anti-aging ingredients, whitening ingredients, amino acids, proteins, and plant extracts. The other physiologically or pharmacologically active ingredients may be used alone or in combination of two or more. In addition, other physiologically or pharmacologically active ingredients can be used within the scope that does not impair the effects of the present invention.

[0041] Anti-inflammatory agents include allantoin, glycyrrhizic acid, glycyrrhetinic acid, prednisolone valerate acetate, dexamethasone acetate, hydrocortisone acetate, ufenamate, bufexamac, ibuprofen piconol, indomethacin, diclofenac, piroxicam, epsilon-aminocaproic acid, berberine, lysozyme, azulene, bromelain, serrapeptase, semi-alkaline proteinase, and pharma- ceutical or physiologically acceptable salts thereof.

[0042] Examples of disinfectants include isopropylmethylphenol, dequalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and biguanide compounds.

[0043] Antifungal agents include terbinafine, naftifine, butenafine, tolnaftate, liranaftate, miconazole, lanoconazole, luliconazole, isoconazole, ketoconazole, clotrimazole, neticonazole, sulconazole, bifonazole, oxiconazole, econazole, fluconazole, itraconazole, fosfluconazole, voriconazole, eficonazole, butoconazole, fenticonazole, and sertaconazole.

[0044] Examples of moisturizing ingredients include polyhydric alcohols such as glycerin, dipropylene glycol, 1,3-butylene glycol, propylene glycol, polyethylene glycol, diglycerin, pentanediol, hexanediol, and octanediol; sugars such as trehalose, xylitol, and sorbitol; polymeric compounds such as sodium hyaluronate, heparinoids, sodium chondroitin sulfate, keratin, chitin, and chitosan; lipids such as ceramide, cholesterol, and phospholipids; and plant extracts such as chamomile extract, witch hazel extract, tea extract, and aloe extract.

[0045] Examples of vitamins include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate, ubiquinone derivatives and their pharma- ceutical or physiologically acceptable salts, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, and benzyl nicotinate. , methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, L-ascorbyl dipalmitate, methylhesperidin, ergocalciferol, cholecalciferol, phylloquinone, farnoquinone, gamma-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine Monophosphate, Thiamine Lysine, Thiamine Triphosphate, Thiamine Monophosphate Phosphate, Thiamine Monophosphate, Thiamine Diphosphate, Thiamine Diphosphate Hydrochloride, Thiamine Triphosphate, Thiamine Triphosphate Monophosphate, Pyridoxine Hydrochloride, Pyridoxine Acetate, Pyridoxal Hydrochloride, Pyridoxal 5'-Phosphate, Pyridoxamine Hydrochloride, Cyanocobalamin, Hydroxocobalamin, Deoxyadenosylcobalamin, Folic Acid, Pteroylglutamic Acid, Nicotinic Acid, Nicotinamide, Pantothenic Acid, Pantothenic Acid, Examples of suitable anti-inflammatory agents include calcium anthraquinone, pantothenyl alcohol (panthenol), D-panthesine, D-pantethine, coenzyme A, pantothenyl ethyl ether and other pantothenic acids, biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, eriocitrin, and pharma- ceutical or physiologically acceptable salts thereof.

[0046] Examples of peptides or derivatives thereof include keratin decomposition peptides, hydrolyzed keratin, collagen, gelatin, elastin, elastin decomposition peptides, collagen decomposition peptides, hydrolyzed collagen, and hydrolyzed silk.

[0047] Preferred examples of blood circulation promoting ingredients include plant-derived ingredients, such as ginseng, angelica, arnica, ginkgo, citrus fruit, oak, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, hawthorn, juniper, cnidium rhizome, swertia japonica, thyme, clove, tangerine, angelica tree, tonin, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, rosemary, rose hip, peach, apricot, walnut, corn, etc. (extracts of these plants, etc.), and glucosyl hesperidin.

[0048] Cell-activating ingredients include amino acids such as gamma-aminobutyric acid, gamma-amino-beta-hydroxybutyric acid, and epsilon-aminocaproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, and biotin, alpha-hydroxy acids such as glycolic acid and lactic acid, tannins, flavonoids, saponin, allantoin, photosensitizer No. 301, placenta extract, hinokitiol, cepharanthin, and kiwi seed extract.

[0049] Anti-aging ingredients include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

[0050] Examples of whitening ingredients include tocopherol, ascorbic acid, tranexamic acid, arbutin, 4-alkylresorcinol, 4-methoxysalicylic acid, hydroquinone, kojic acid, salts thereof, or derivatives thereof, and plant extracts such as placenta extract, Phellodendron Bark extract, Saxifrage extract, and Aloe extract.

[0051] The composition for external use of the present invention may further contain a keratin softening agent. Examples of the keratin softening agent include ethyl alcohol, isopropyl alcohol, propanol, butanol, 1,3-butylene glycol, propylene glycol, polyethylene glycol (macrogol), glycerin, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyldodecanol, allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurate, lanolin, fatty acid dialkylolamide, salicylic acid, salicylic acid derivatives, urea, sulfur, resorcin, glycolic acid, phytic acid, lactic acid, lactate, sodium hydroxide, potassium hydroxide, etc. On the other hand, in one embodiment, the topical composition of the present invention may be a topical composition that does not contain such a keratin softening agent. In particular, an embodiment that does not contain urea is exemplified. A topical composition that does not contain a keratin softening agent is preferable because it places less strain on the skin.

[0052] Base or Carrier The base or carrier may be an oily base or an aqueous base. Oily bases include hydrocarbons such as liquid paraffin, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, and light liquid paraffin; silicone oils such as methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl modified silicone, crosslinked alkyl modified silicone, amino modified silicone, polyether modified silicone, polyglycerin modified silicone, crosslinked polyether modified silicone, crosslinked alkyl polyether modified silicone, silicone / alkyl chain co-modified polyether modified silicone, silicone / alkyl chain co-modified polyglycerin modified silicone, polyether modified branched silicone, polyglycerin modified branched silicone, acrylic silicone, phenyl modified silicone, and silicone resin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; cholesterol, phytosterol, and phytostearate hydroxystearate. sterols such as teryl; vegetable fats such as shea butter, carnauba wax, and candelilla wax; animal fats and oils such as lanolin, orange roughy oil, squalane, horse fat, spermaceti, and beeswax; natural polymer derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, cationic guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymers, and alkyl acrylate / methacrylate copolymers; natural polymers such as carrageenan, alginic acid, cellulose, xanthan gum, guar gum, quince seed, dextran, gellan gum, and hyaluronic acid; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra 2-ethylhexanoate, and caprylic / capric triglyceride; polysaccharides such as dextrin and maltodextrin;Examples of glycol ethers include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether. In addition to water and buffer solutions, aqueous bases include lower alcohols such as ethanol and isopropanol; and polyhydric alcohols such as polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, isoprene glycol, diglycerin, and dipropylene glycol. The substrate or carrier may be used alone or in combination of two or more.

[0053] The base or carrier is preferably a hydrocarbon, a higher alcohol, a natural polymer derivative, a synthetic polymer, a natural polymer, an ester, or a polyhydric alcohol. The content of a hydrocarbon as a base or carrier is, for example, 0.1 to 20% by weight, preferably 1 to 15% by weight, based on the total amount of the composition. The content of a higher alcohol as a base or carrier is, for example, 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total amount of the composition. The content of a natural polymer derivative as a base or carrier is, for example, 0.01 to 5% by weight, preferably 0.05 to 3% by weight, based on the total amount of the composition. The content of a synthetic polymer as a base or carrier is, for example, 0.01 to 5% by weight, preferably 0.1 to 3% by weight, based on the total amount of the composition. The content of a natural polymer as a base or carrier is, for example, 0.01 to 3% by weight, preferably 0.05 to 1% by weight, based on the total amount of the composition. The content of an ester as a base or carrier is, for example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, based on the total amount of the composition. When a polyhydric alcohol is contained as a base or carrier, the content thereof is, for example, 0.1 to 20% by weight, and preferably 0.5 to 10% by weight, based on the total amount of the composition.

[0054] The composition of the present invention may be water-free and may be made into an emulsion using an aqueous base other than water, but it is preferred that the composition contains water. The water content can be 0.1% by weight or more, 1% by weight or more, 5% by weight or more, 10% by weight or more, 30% by weight or more, or 45% by weight or more based on the total weight of the composition. The water content can be 95% by weight or less, 90% by weight or less, or 80% by weight or less based on the total weight of the composition. Within this range, the emulsion containing the vegetable oil is sufficiently stable.

[0055] The composition of the present invention is an emulsified composition. The type of emulsion may be either an oil-in-water type or a water-in-oil type, but the oil-in-water type is preferred in terms of improving the stability of an emulsion containing a vegetable oil. The dosage form of the present invention may be any emulsion dosage form, including lotions (milky lotions), creams, gels, foams, emulsion ointments, patches in which these are applied to a substrate, inhalants, nasal drops (including nasal sprays), etc. Among these, topical preparations such as lotions, creams, and patches in which these are applied to a substrate are preferred, lotions and creams are more preferred, and creams are particularly preferred. The composition for external use of the present invention can be applied to the skin or mucous membrane, and is particularly preferably a composition for external use on the skin. The skin includes the scalp.

[0056] The pH of the composition of the present invention can be 3 or more, 4 or more, 4.5 or more, or 5 or more, and can be 9 or less, 8 or less, 7.5 or less, or 7 or less. Within these ranges, the emulsified state is stable and irritation is minimal.

[0057] Applies to The topical composition of the present invention is preferably used for symptoms or diseases for which antihistamines have a therapeutic, preventive or ameliorative effect. Examples of such symptoms or diseases include diseases that show itching symptoms or symptoms caused by dry skin. Examples of diseases that show itching symptoms or symptoms caused by dry skin include xerosis, senile xerosis, pediatric dry skin, leiomyosa vulgaris (shark skin), atopic dermatitis, allergic dermatitis, seborrheic eczema, sensitive skin, seasonal xerosis, aqueous pruritus, housewives' eczema, dermatitis, rash, hives, insect bites, eczema, sores, heat rash, chilblains, etc.

[0058] Methods for preventing phase separation and stabilizing the emulsion state The present invention includes a method for suppressing phase separation of a topical composition, which is an emulsion containing a vegetable oil, by adding an antihistamine to the composition. Phase separation is a state in which a part or all of an emulsified composition is separated into an aqueous phase and an oil phase. Phase separation also includes a state in which emulsified droplets at least partially coalesce and become larger. The present invention also encompasses a method for stabilizing the emulsified state of a topical composition that is an emulsion containing a vegetable oil, or a method for improving the stability of the composition, by incorporating an antihistamine into the composition. If the presence of an antihistamine can detectably reduce or delay phase separation, this corresponds to inhibition of phase separation.Also, if the presence of an antihistamine can detectably reduce or delay the destruction or change of the emulsified state, extend the duration of the emulsified state, or enable the emulsified state to be maintained under harsher conditions, this corresponds to stabilization or improvement of stability.

[0059] The present invention also includes a method for suppressing phase separation of an external composition, which is an emulsion containing an antihistamine, by adding a vegetable oil to the composition. The present invention also includes a method for stabilizing the emulsified state of an external composition, which is an emulsion containing an antihistamine, or a method for improving the stability of the composition, by adding a vegetable oil to the composition. If the presence of the vegetable oil can detect a reduction or delay in phase separation, this corresponds to suppression of phase separation. If the presence of the vegetable oil can detect a reduction or delay in the destruction or change of the emulsified state, extend the time the emulsified state is maintained, or the emulsified state is maintained under harsher conditions, this corresponds to stabilization or improvement of stability.

[0060] In these methods of the present invention, the type and amount of each component, the formulation type of the composition, pH, etc. are as explained for the topical composition of the present invention. EXAMPLES

[0061] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these. (1) Evaluation of storage stability (thermal stability) A composition for external use (oil-in-water cream) having the composition shown in Table 1 was prepared according to a conventional method. 50 g of each of the compositions of the Examples and Comparative Examples was placed in a glass screw-cap bottle (volume: 50 mL) and stored in the dark at 50° C. or 60° C. for one week.

[0062] The properties of the composition before and after storage were visually observed, and the degree of phase separation of the composition was evaluated according to the following criteria. <Separation evaluation criteria> ◎: No separation at all, stable ○: A small amount of liquid is visible on the surface of the preparation. △: Separated liquid can be seen on the surface of the preparation and on the periphery of the bottle. ×: Part of the preparation has turned into liquid and is clearly separated.

[0063] The results are shown in Table 1. All units in Table 1 are "% by weight" unless otherwise stated in the table. [Table 1]

[0064] Storage tests at 50°C or 60°C allow evaluation of thermal stability and also enable prediction and evaluation of stability when stored at room temperature. In the preparations containing lavender oil or eucalyptus oil, the aqueous phase and the oil phase were separated after storage (Comparative Example 1-2, Comparative Example 1-3). In addition, the preparation containing diphenhydramine also separated into the aqueous phase and the oil phase after storage (Comparative Example 1-1). On the other hand, the preparations containing lavender oil or eucalyptus oil and diphenhydramine (Example 1-1, Example 1-2), and the preparations containing lavender oil, eucalyptus oil and diphenhydramine (Example 1-3) did not undergo phase separation. It can be seen that the synergistic action of lavender oil and / or eucalyptus oil and diphenhydramine suppressed phase separation of the emulsion.

[0065] (2) Evaluation of storage stability (photostability) Compositions for external use (oil-in-water creams) of Examples 2-1 to 2-3 and Comparative Examples 2-1 to 2-3 shown in Table 2 were prepared according to a conventional method. 50 g of each composition of the Examples and Comparative Examples was placed in a glass screw-cap bottle (volume 50 mL) and measured at 725 W / m 2 The cells were exposed to light for 48 hours under the above conditions. The properties of the compositions were visually observed before and after light irradiation, and the degree of separation of each composition was evaluated according to the same criteria as in "(1) Evaluation of storage stability (thermal stability)". The results are shown in Table 2. All units in Table 2 are "% by weight" unless otherwise stated in the table.

[0066] [Table 2]

[0067] In the preparations containing lavender oil or eucalyptus oil, the aqueous phase and the oil phase were separated after light irradiation (Comparative Example 2-2, Comparative Example 2-3). In addition, the preparation containing diphenhydramine also separated into the aqueous phase and the oil phase after storage (Comparative Example 2-1). On the other hand, the preparations containing lavender oil or eucalyptus oil and diphenhydramine (Example 2-1, Example 2-2), and the preparations containing lavender oil, eucalyptus oil and diphenhydramine (Example 2-3) did not undergo phase separation. It can be seen that the synergistic action of lavender oil and / or eucalyptus oil and diphenhydramine suppressed phase separation of the emulsion.

[0068] (3) Evaluation of storage stability (thermal stability, light stability) Compositions for external use having the compositions shown in Table 3 (Examples 3-1 to 3-5: oil-in-water creams, Example 3-6: oil-in-water lotion) were prepared according to a conventional method. 50 g of each composition of the Examples was placed in a glass screw-cap bottle (volume 50 mL) and stored in a dark place at 50° C. or 60° C. for one week. In addition, 50 g of each composition of the Examples was placed in a glass screw-cap bottle (volume 50 mL) and measured at 725 W / m 2 The cells were exposed to light for 48 hours under the above conditions. The properties of the compositions were visually observed before and after storage and before and after light irradiation, and the degree of separation of each composition was evaluated according to the same criteria as in "(1) Evaluation of storage stability (thermal stability)".

[0069] The results are shown in Table 3. In Table 3, all units are "% by weight" unless otherwise stated in the table. [Table 3]

[0070] It was confirmed that no phase separation occurred after storage at high temperatures of 50°C or 60°C or after exposure to light, even when the diphenhydramine content, the lidocaine content, the vegetable oil content, the antihistamine diphenhydramine hydrochloride content instead of diphenhydramine, or the lotion formulation.

[0071] Formulation examples Compositions for external use of the present invention containing an antihistamine and a vegetable oil were prepared according to the formulations shown in Tables 4 and 5 (Formulation Examples 1 to 10). Formulation Examples 1 to 4 are creams, and Formulation Examples 5 to 10 are lotions. The units in Tables 4 and 5 are all "% by weight" unless otherwise stated in the tables.

[0072] [Table 4]

[0073] [Table 5] [Industrial Applicability]

[0074] The composition for external use of the present invention can enhance the stability of the emulsion state without relying solely on additives such as emulsifiers and thickeners, and therefore has a high degree of freedom in formulation design and is of high commercial value.

Claims

1. A composition for external use which is an emulsion (excluding the case where luliconazole and / or a pharma- ceutically acceptable salt thereof is contained), comprising: (i) diphenhydramine and / or a salt thereof; (ii) 0.001 to 1 part by weight of an essential oil per 1 part by weight of diphenhydramine and / or a salt thereof; (iii) at least one member selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acids, polyglycerin fatty acids, propylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monococonut oil glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether, stearylamine, oleylamine, hydrocarbons, and oily esters; and (iv) water.

2. The composition for external use according to claim 1, wherein the content of diphenhydramine and / or a salt thereof is 0.01 to 5% by weight based on the total amount of the composition for external use.

3. 3. The composition for external use according to claim 1 or 2, wherein the content of the essential oil is 0.0001 to 1% by weight based on the total amount of the composition for external use.

4. An emulsion stabilizer for a topical composition which is an emulsion containing an essential oil and is used so that the ratio of the content of the essential oil to 1 part by weight of diphenhydramine and / or a salt thereof is 0.001 to 1 part by weight (excluding the case where the topical composition contains luliconazole and / or a pharma- ceutically acceptable salt thereof), (a) diphenhydramine and / or a salt thereof, (c) at least one member selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acids, polyglycerin fatty acids, propylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monococonut oil glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether, stearylamine, oleylamine, hydrocarbons, and oily esters, and (d) water.

5. An emulsion stabilizer for a topical composition which is an emulsion containing diphenhydramine and / or a salt thereof and is used such that the ratio of the content of the essential oil to 1 part by weight of diphenhydramine and / or a salt thereof is 0.001 to 1 part by weight (b) an essential oil, (c) at least one selected from the group consisting of sorbitan fatty acid esters, glycerin fatty acids, polyglycerin fatty acids, propylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monococonut oil glyceryl, glycerin alkyl ether, alkyl glucoside, polyoxyethylene cetyl ether, stearylamine, oleylamine, hydrocarbon, and oily esters, and (d) water (excluding the case where the topical composition contains luliconazole and / or a pharma- ceutically acceptable salt thereof).

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